Born from Two Fathers

Researchers at Kyushu University in Japan recently demonstrated that mice can be conceived with two genetic fathers, opening up future opportunities for assisted reproduction and animal conservation, and posing serious ethical questions.

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By Stacey Chen

In your freshman biology class, you likely learned that every baby begins with an egg and a sperm. But what if genetic engineering technology made it possible to produce a viable embryo without an egg? Could a baby have two biological fathers? Japanese researchers have demonstrated that, at least in mice, this is a real possibility.

Researchers at Kyushu University successfully raised mice conceived using genetic material from two male mice, proving that a genetic mother is not needed for mice to produce a baby. To do this, the researchers had to overcome several obstacles. First, the scientists needed an egg, which, when fertilized by a sperm, would develop into an embryo and then into a baby. Since male mice do not produce eggs, the researchers utilized stem cells, which are non-specialized cells that can become any type of cell. To obtain the stem cells, the researchers introduced four specific genes—Myc, Oct3/4, Sox2, and Klf4—into the skin cells from the tail of a male mouse. When inserted into somatic (neither sperm nor egg) cells, these genes create proteins that cause them to revert to the stem cell stage, allowing them to develop into other types of cells.

However, these cells cannot develop into ova (mature female reproductive cells) yet because each cell has genetic material, including sex chromosomes, that influences how it can develop. Cells from males have XY sex chromosomes, while those from females have XX sex chromosomes; egg cells can only develop cells with the XX genotype. Thus, the scientists had to remove the Y chromosome from the male cells and induce them to duplicate their existing X chromosomes. Then, the researchers placed the modified stem cells into a culture containing ovary cells, whose hormones encouraged the stem cells to develop into ova.

Finally, a sperm fertilized the modified egg cells, and the resulting embryos gestated, or developed, inside a surrogate mother. The researchers produced 630 embryos, of which only seven resulted in successful, full-term births. All seven mice grew up without complications, and even appear to be fertile.

It is not the first time scientists have produced healthy mice pups from the gametes (reproductive cells) of same-sex parents, but it is the first successful experiment featuring two fathers. In 2004, Japanese scientists successfully conceived mice by combining the nuclei of eggs from two mothers, resulting in full-term births. Normally, embryo development requires a chromosome from both a male and a female because different genes are active depending on the sex of the parent. An embryo needs genetic signals from the chromosomes of both sexes to develop properly, regardless of the embryo’s own sex. To circumvent this, the researchers removed two genes from a female’s X chromosome so that it more closely resembled a male chromosome, allowing for the embryo to develop further.

In 2018, Chinese researchers completed the same experiment, but removed the third gene, which resulted in mice that had fewer developmental problems. The Chinese team also attempted to inject modified DNA from two male mice into an egg cell, but that prevented normal development and caused early death for the offspring. The Kyushu study used the knowledge from the Chinese study and opted to use stem cells rather than modifying the genetic material of an existing egg.

Unlike the previous experiments, the Kyushu team’s process yielded no apparent abnormalities, albeit with a success rate of only one percent. The experiments have far-reaching implications, as the usage of stem cells and same-sex gametes to produce viable embryos could one day extend to humans, potentially bringing reproductive liberty to many. It could allow people to conceive children using DNA from one of their body cells, providing male same-sex couples or those struggling with fertility the choice to have children without an egg donor. Similarly, the gene modification process could allow people to combine two eggs to have a child, which could help female same-sex couples conceive. In addition, the manipulation of chromosomes is promising for those with chromosomal abnormalities; by removing extraneous chromosomes in their gametes, they could maximize chances of having healthy children.

The technology could also be used to conserve endangered species when there are not enough members of the opposite sex remaining. If a species survived with only male members, scientists could theoretically produce eggs from the somatic cells of males. If these eggs could develop in the womb of a related species, it could restore the population of the endangered species. Similarly, if a species survived with only female members, researchers could use the procedure from the 2018 study to create new individuals, though this method would be limited to producing only female offspring.

However, the team notes that the human applications of this technology lie decades in the future, if not centuries. First of all, it is still being determined how the process would differ between humans and mice. Researchers have studied mice genomes and stem cells for years, but lack the same knowledge of the complicated processes of human reproduction. In addition, the researchers noted an increase in the number of genetic mutations present in offspring conceived through these means, posing serious ethical concerns. Though they did not report any significant side effects in the mice, humans have longer and more chromosomes, which would accumulate more mutations and consequently pose a greater risk of severe genetic defects.

Aside from the high risk, these technologies would likely be expensive and inaccessible to large populations of people. Only a select few would be able to participate, especially since many jurisdictions around the world regulate and even ban editing the human genome. 

The main public concern is the ethical issues that would arise when this technology is applied to human reproduction. The procedure’s one percent success rate in mice could cause hundreds of human embryos to die for every embryo carried to term. Even after birth, there would be endless questions about the effects of these embryonic experiments on long-term health, resulting in constant medical monitoring for research purposes. Not to mention what would happen if serious long-term health consequences arose, which is likely impossible to predict.

Overall, the usage of stem cells to allow male same-sex mice to have babies opens up doors to new possibilities and also major issues. Though this discovery could progress into reproductive liberty for many and the conservation of endangered species, serious ethical concerns are raised surrounding the procedure’s high risk and low success rate; it is clear that this avenue must be navigated slowly and carefully if humans have any hope of responsibly integrating these methods for their own reproduction purposes.